Asymmetric Aldol Reaction of α,α-Disubstituted Acetaldehydes Catalyzed by Diphenylprolinol Silyl Ether for the Construction of Quaternary Stereogenic Centers

Article abstract of DOI:10.1002/ejoc.201500585

The asymmetric cross-aldol reaction of α,α-disubstituted acetaldehydes with commercial ethyl glyoxylate polymer was successfully catalyzed by diphenylprolinol silyl ether 3 to generate all-carbon quaternary stereogenic centers with good enantioselectivity. Diphenylprolinol silyl ether is an effective organocatalyst in the asymmetric cross-aldol reaction of α,α-disubstituted acetaldehydes with commercial ethyl glyoxylate polymer to generate all-carbon quaternary stereogenic centers with good enantioselectivity.

Full text of DOI:10.1002/ejoc.201500585

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500585
Asymmetric Aldol Reaction of α,α-Disubstituted Acetaldehydes Catalyzed by
Diphenylprolinol Silyl Ether for the Construction of Quaternary Stereogenic
Centers
Yujiro Hayashi,*[a] Hiroki Shomura,[a] Qianqian Xu,[a] Martin J. Lear,[a][‡] and
and Itaru Sato[a][‡‡]
Keywords: Organocatalysis / Asymmetric synthesis / Aldol reactions / Quaternary stereogenic center
The asymmetric cross-aldol reaction of α,α-disubstituted
acetaldehydes with commercial ethyl glyoxylate polymer
was successfully catalyzed by diphenylprolinol silyl ether 3
to generate all-carbon quaternary stereogenic centers with
good enantioselectivity.
The aldol reaction is one of the most useful carbon–car- and Barbas reported the aldol reaction catalyzed by the
bon bond forming reactions in organic chemistry.[1] After combination of a diamine and an acid.[14] Although excel-
the pioneering discovery of the intermolecular proline-me- lent enantioselectivity was obtained, only p-nitrobenzalde-
diated aldol reaction of aldehydes and ketones by List, Ler- hyde was examined as the electrophilic aldehyde. Mahrwald
ner and Barbas in 2000, there has been great progress in reported the aldol reaction catalyzed by histidine, which af-
the field of organocatalysed asymmetric aldol chemistry.[2] forded the aldol product with moderate to good enantio-
The cross aldol reaction of two different aldehydes cata- selectivity.[15] Compared to the aldol reaction of α-mono-
lyzed by proline was reported by MacMillan in 2002.[3] Al- substituted acetaldehydes, the reaction of α,α-disubstituted
though the generated β-hydroxy aldehydes are synthetically acetaldehydes is significantly more difficult. Herein, we dis-
useful and versatile chiral building blocks, the reaction is close the asymmetric aldol reaction of a range of α,α-aryl,
often limited to particular aldehydes. Our group has contin- alkyl disubstituted acetaldehydes with commercial ethyl
uing interest to develop a general organocatalyst for the glyoxylate.
asymmetric cross-aldol reaction of aldehydes. Through our
Ethyl glyoxylate is a useful electrophilic aldehyde, be-
efforts, we have found trifluoromethyl-substituted diaryl- cause it possesses an ester moiety that can be converted into
prolinol as an effective organocatalyst in the aldol reaction other functional groups.[16] Due to practical reasons, we
of not only acetaldehyde as the pro-nucleophile,[4] but also have already adopted the direct use of commercially avail-
ethyl glyoxylate,[5] chloroacetaldehye,[6] trifluoroacetal- able polymer solutions of ethyl glyoxylate in the asymmetric
dehyde ethyl acetal,[7] pyruvaldehyde,[8] succinaldehyde,[9] aldol reaction of mono-substituted acetaldehydes catalyzed
glyoxal,[10] alkynyl aldehyde,[11] and formaldehyde[12] as the by diarylprolinol.[5] We thus began to investigate the aldol
electrophilic aldehyde.
reaction of commercial ethyl glyoxylate with α,α-disubsti-
An equally continuing challenge for contemporary syn- tuted acetaldehydes. For this purpose, 2-phenylpropanal
thetic organic chemistry is the asymmetric synthesis of all- was selected as a model nucleophilic aldehyde. First, the
carbon quaternary stereogenic centers.[13] In this context, optimal catalyst was surveyed (Figure 1). Although diaryl-
there have been only two reports, as far as we are aware, prolinol 1 is an effective catalyst in other aldol reactions of
that describe the intermolecular asymmetric aldol reaction α-mono-substituted acetaldehydes,[5–12] it afforded products
to form all-carbon quaternary stereogenic centers. Tanaka with low enantioselectivity (Table 1, entry 1). Use of the
silyl ether 2 gave better results. As the reaction was slow,
[a] Department of Chemistry, Graduate School of Science, Tohoku
University,
6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
E-mail: yhayashi@m.tohoku.ac.jp
http://www.ykbsc-chem.com/
[‡] Present address: School of Chemistry, University of Lincoln,
Brayford Pool, Lincoln, Lincolnshire, LN6 7TS, United
Kingdom
[‡‡] Present address: Faculty of Science, Ibaraki University,
2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500585.
Figure 1. Catalysts examined in this study.
4316
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4316–4319

Asymmetric Aldol Reactions
Table 1. Effect of catalyst and solvent in the asymmetric aldol reac- the reaction was performed at 50 °C. This afforded the
tion of 2-phenylpropanal and ethylglyoxylate.[a]
product in 70% yield with good enantioselectivity (80% ee,
syn isomer, entry 2). By altering the silyl group on the cata-
lyst, the reaction could be conducted at room temperature
with good enantioselectivity by employing the diphenylpro-
linol silyl ether 3, a catalyst developed independently by our
group[17] and that of Jørgensen.[18] The trimethylsilyl, tert-
butyldimethylsilyl and triisopropylsilyl ethers 3–5 gave simi-
larly good enantioselectivity (entries 3–5). Next, the solvent
was investigated using diphenylprolinol trimethylsilyl ether
3 as the catalyst (entries 6–10). While the reaction barely
Entry Catalyst Solvent Time [h] Yield [%][b] syn/anti[c] ee [%][d]
proceeded in MeOH, a lower enantioselectivity was ob-
tained in CH2Cl2 and MeCN. Reactions in DMF gave a
1[e]
2[e]
3
4
5
6
7
8
9
1
2
3
4
5
3
3
3
3
3
toluene
toluene
toluene
toluene
toluene
MeOH
CH2Cl2
MeCN
DMF
48
48
24
36
48
96
15
28
10
18
44
70
86
72
65
Ͻ 5
55
84
93
86
1:2.3
1:1.4
1:1.3
1:1.1
1:1.2
12:54
80:3
74:44
71:59
73:35
Table 3. Asymmetric aldol reaction of α,α-disubstituted acetalde-
hyde and ethyl glyoxylate.[a]
1:1.1
1:1
1:1.2
1:1.3
39:11
59:28
71:41
82:13
10
THF
[a] Unless noted otherwise, reactions were performed by employing
a 47% toluene solution of ethyl glyoxylate polymer (0.46 mmol,
100 mg), 2-phenylpropanal (0.23 mmol) and organocatalyst
(0.069 mmol, 30 mol-%) in the solvent (0.23 mL) at room tempera-
ture for the indicated time. [b] Yield of purified aldol product. [c]
Diastereomer ratio, as determined by 1H-NMR spectroscopy. [d]
ee of the syn- and anti-aldol products, as determined by HPLC
analysis over a chiral solid phase. [e] Reaction performed at 50 °C.
Table 2. Effect of additives in the asymmetric aldol reaction of 2-
phenylpropanal and ethylglyoxylate.[a]
Entry Additive
Time [h] Yield [%][b] syn/anti[c] ee [%][d]
1
2
3
4
5
6
none
p-nitrophenol
AcOH
18
8
4
4
1.5
3
86
75
75
72
75
83
1:1.3
1:1.2
1:1.5
1:1.2
1:1.3
1:1.2
82:13
58:26
68:6
62:2
65:40
86:58
PhCO2H
ClCH2CO2H
N,NЈ-bis[3,5-bis(tri-
fluoro-methyl)-
phenyl]thiourea
[a] Unless noted otherwise, reactions were performed by employing
a 47% toluene solution of ethyl glyoxylate polymer (0.46 mmol,
[a] Unless noted otherwise, reactions were performed by employing
a 47% toluene solution of ethyl glyoxylate polymer (0.46 mmol,
100 mg), nucleophilic aldehyde (0.23 mmol), organocatalyst
3
100 mg), 2-phenylpropanal (0.23 mmol), organocatalyst
2
(0.069 mmol, 30 mol-%) and thiourea derivative (0.069 mmol,
30 mol-%) in THF (0.23 mL) at room temperature for the indicated
time. [b] Isolated yield of purified aldol product. [c] Diastereomer
ratio, as determined by 1H-NMR spectroscopy. [d] ee of the anti
and syn aldol product, as determined by HPLC analysis over a
chiral solid phase.
(0.069 mmol, 30 mol-%), and additive (0.069 mmol) in THF
(0.23 mL) at room temperature for the indicated time. [b] Yield of
purified aldol product. [c] Diastereomer ratio, as determined by
1H-NMR spectroscopy. [d] ee of the syn- and anti-aldol products,
as determined by HPLC analysis over a chiral solid phase.
Eur. J. Org. Chem. 2015, 4316–4319
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4317

Y. Hayashi, H. Shomura, Q. Xu, M. J. Lear, I. Sato
SHORT COMMUNICATION
similarly good enantioselectivity to toluene. Optimal enecarbaldehyde gave moderate enantioselectivity (entry 6),
enantioselectivity was realized in THF, which afforded the while the reaction of 2,3-dihydaro-1H-indene-1-carbal-
product in 82% ee as for a syn isomer.
dehyde gave high enantioselectivity (entry 7).
Although the best catalyst and solvent were determined,
The relative and absolute configurations of the aldol
the reaction proceeded slowly over 18 hours before comple- products were determined as follows: Aldol product of 2-
tion. As acid is sometimes effective in facilitating organoca- phenylpropanal was reduced by NaBH4 to afford diol,
talyst-mediated reactions, additives were examined next which was converted into lactone by the acid treatment, see
(Table 2). The reaction was found to be accelerated in the Equation (1). cis and trans isomers were separated and then
presence of acids such as p-nitrophenol, acetic acid, benzoic converted into MTPA esters by treatment with (R)- and (S)-
acid and chloroacetic acid, but the enantioselectivity de- MTPA-Cl. The absolute configurations were determined by
creased (entries 2–5). For instance, the reaction completed comparison of literature data[15] and by the use of Kakis-
within 1.5 h in the presence of chloroacetic acid, but the awa–Kusumi’s modification of Mosher method.[20]
enantioselectivity of the syn isomer was 65%. Instead of
acid, Schreiner’s thiourea[19] was selected as an additive.
Here, the reaction not only accelerated, but also the
enantioselectivity increased to 86%. As anticipated, the
thiourea derivative presumably facilitated the reaction via
hydrogen-bond activation of the ethyl ester carbonyl moi-
ety.
Having determined optimal reaction conditions, the gen-
erality of the reaction was investigated as summarized in
Table 3. As for the aryl substituent of 2-arylpropanal acting
as a pro-nucleophilic aldehyde, not only phenyl, but also
phenyl groups substituted with electron-rich substituents
such as p-methoxyphenyl and 3,4-dimethoxyphenyl were
(1)
The relative stereochemistries of the aldol products of
found suitable to afford the aldol products with good 1,2,3,4-tetrahydro-1-naphthalenecarbaldehyde and 2,3-di-
enantioselectivity (entries 2, 3). In the reaction of electron- hydro-1H-indene-1-carbaldehyde were determined by the
deficient aryl moieties, such as 2-(p-chlorophenyl) and 2-(p- NOE analysis of the corresponding lactone, generated by
bromophenyl)propanal, the enantioselectivity was moderate the reduction with NaBH4 and acid treatment; see Equa-
(entries 4,5). The reaction of 1,2,3,4-tetrahydro-1-naphthal- tions (2) and (3).
Scheme 1. Proposed reaction mechanism of 2-phenylpropanal and ethyl glyoxylate catalyzed by diphenylprolinlol silyl ether 3.
4318
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4316–4319

Asymmetric Aldol Reactions
[1] Modern Aldol Reactions, vol. 1, 2 (Ed.: R. Mahrwald), Wiley-
VCH, Weinheim, Germany, 2004.
[2] B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395.
(2)
(3)
[3] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798.
[4] a) Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem.
Int. Ed. 2008, 47, 2082; Angew. Chem. 2008, 120, 2112; b) Y.
Hayashi, S. Samanta, T. Itoh, H. Ishikawa, Org. Lett. 2008, 10,
5581; c) T. Itoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2009, 11,
3854.
[5] T. Urushima, Y. Yasui, H. Ishikawa, Y. Hayashi, Org. Lett.
2010, 12, 2966.
[6] Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa,
Angew. Chem. Int. Ed. 2011, 50, 2804; Angew. Chem. 2011, 123,
2856.
Since the chirality at the α-position of the ester moiety was
found to be R in both the syn- and anti-isomers, the Re-face [7] Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa,
Synlett 2011, 485.
of the formyl moiety of ethyl glyoxylate reacts preferentially.
An NMR study of 2-phenylpropanal with diphenylprolinol
[8] Y. Hayashi, Y. Yasui, M. Kojima, T. Kawamura, H. Ishikawa,
Chem. Commun. 2012, 48, 4570.
silyl ether indicated the generation of both E- and Z-en-
[9] Y. Hayashi, K. Nishino, I. Sato, Chem. Lett. 2013, 42, 1294.
amines in nearly equal amounts, see Equation (4). We thus
propose the reaction mechanism shown in Scheme 1.
[10] Y. Hayashi, M. Kojima, ChemCatChem 2013, 5, 2883.
[11] Y. Hayashi, M. Kojima, Y. Yasui, Y. Kanda, T. Mukaiyama,
H. Shomura, D. Nakamura, Ritmaleni, I. Sato, ChemCatChem
2013, 5, 2887.
[12] Y. Yasui, M. Benohoud, I. Sato, Y. Hayashi, Chem. Lett. 2014,
43, 556.
[13] a) M. Bella, T. Gasperi, Synthesis 2009, 1583; b) C. Hawner,
A. Alexakis, Chem. Commun. 2010, 46, 7295; c) J. P. Das, I.
Marek, Chem. Commun. 2011, 47, 4593; d) K. W. Quasdorf,
L. E. Overman, Nature 2014, 516, 181; e) L. Zhang, N. Fu, S.
Luo, Acc. Chem. Res. 2015, 48, 986.
[14] N. Mase, F. Tanaka, C. F. Barbas III, Angew. Chem. Int. Ed.
2004, 43, 2420; Angew. Chem. 2004, 116, 2474.
(4)
[15] a) U. Scheffler, R. Mahrwald, J. Org. Chem. 2012, 77, 2310; b)
Y. Lam, K. N. Houk, U. Scheffler, R. Mahrwald, J. Am. Chem.
Soc. 2012, 134, 6286.
[16] a) D. A. Evans, D. W. C. MacMillan, K. R. Campos, J. Am.
Chem. Soc. 1997, 119, 10859; b) V. B. Gondi, M. Gravel, V. H.
Rawal, Org. Lett. 2005, 7, 5657; c) T. Kano, Y. Yamaguchi, K.
Maruoka, Chem. Eur. J. 2009, 15, 6678; d) F. Pesciaioli, P.
Righi, A. Mazzanti, C. Gianelli, M. Mancinelli, G. Bartoli, G.
Bencivenni, Adv. Synth. Catal. 2011, 353, 2953.
[17] a) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem.
Int. Ed. 2005, 44, 4212; Angew. Chem. 2005, 117, 4284; b) H.
Gotoh, Y. Hayashi, Diarylprolinol Silyl Ethers, Development
and Application as Organocatalysts, in: Sustainable Catalysis
(Eds.: Dunn, K. K. Hii, M. J. Krische, M. T. Williams), John
Wiley & Sons, New Jersey, 2013, p. 287–316; c) Y. Hayashi, D.
Okamura, T. Yamazaki, Y. Ameda, H. Gotoh, S. Tsuzuki, T.
Uchimaru, D. Seebach, Chem. Eur. J. 2014, 20, 17077.
[18] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2005, 44, 794; Angew. Chem. 2005, 117,
804; b) H. Jiang, L. Albrecht, G. Dickmess, K. L. Jensen, K. A.
Jørgensen, TMS-Prolinol Catalyst in Organocatalysis, in: Com-
prehensive Enantioselective Organocatalysis, vol. 1 (Ed.: P. I.
Dalko), Wiley-VCH, Weinheim, Germany, 2013, p. 33–50.
[19] a) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217; combi-
nation of organocatalyst and thiourea as a catalyst in aldol
reaction, see: b) O. Reis, S. Eymur, B. Reis, A. S. Demir, Chem.
Commun. 2009, 1088; c) X. Companyo, G. Valero, L. Crovetto,
A. Moyano, R. Rios, Chem. Eur. J. 2009, 15, 6564; d) G. Ma,
A. Bartoszewicz, I. Ibrahem, A. Cordova, Adv. Synth. Catal.
2011, 353, 3114.
Diphenylprolinol silyl ether 3 reacts with 2-phenylpro-
panal to generate both E- and Z-enamines. Both enamines
react with ethyl glyoxylate from the opposite face of the
bulky diphenylsiloxymethyl moiety to afford iminium ions,
which are hydrolyzed with water to afford the aldol prod-
ucts. As both enamines react readily, the diastereoselectivity
is not high. Because the bulky diphenylsiloxymethyl covers
one of the enantiofaces of the enamine-catalyst intermedi-
ate,[17c] high enantioselectivity results in the aldol products.
In conclusion, we have developed a practical synthesis of
chiral β-hydroxy-α,α-disubstituted aldehydes via an asym-
metric, direct aldol reaction of α,α-disubstituted acetalde-
hydes, catalyzed by the diphenylprolinol silyl ether 3. There
are several noteworthy features of this reaction method: (1)
Schreiner’s thiourea is found to be an effective co-catalyst
that not only accelerates the reaction, but also increases the
enantioselectivity. (2) Synthetically useful all-carbon qua-
ternary stereogenic centers can be constructed with good
enantioselectivity.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas Advanced Molecular Transformations by Or-
ganocatalysts from The Ministry of Education, Culture, Sports, Sci-
ence and Technology (MEXT), Japan, and the Multidimensional
Materials Science Leaders Program (grant to M. J. L.).
[20] I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem.
Soc. 1991, 113, 4092.
Received: May 8, 2015
Published Online: June 5, 2015
Eur. J. Org. Chem. 2015, 4316–4319
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4319